Glutamate is an excitatory neurotransmitter that binds to the kainate receptor (KAR), the N-methyl-D-aspartate receptor (NMDAR), and the alpha(α)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Each receptor was first characterized and cloned in the central nervous system (CNS). Glutamate is also present in the periphery, and glutamate receptors have been identified in non-neuronal tissues, including bone, heart, kidney, pancreas, and platelets.
Platelets play a central role in normal thrombosis and hemostasis, as well as contributing greatly to diseases such as stroke and myocardial infarction. Cardiovascular disease and stroke are major causes of morbidity and mortality. Although many pathophysiologic processes play a role in the chronic development of cardiovascular disease, thrombosis is often the event that precipitates stroke and acute coronary syndromes. Thrombosis is initiated by receptors on resting platelets that respond to activation initiators such as von Willebrand factor (vWf), thrombin, adenosine diphosphate (ADP), and collagen. Blood glutamate concentration is relatively high compared to the concentration in the central nervous system (CNS), and it is tightly controlled by peripheral glutamate transporters. Platelets express glutamate uptake transporters (EAATs) to clear glutamate from the extracellular environment and vesicular glutamate (vGlut) transporters to load glutamate into granules. It has been demonstrated in studies using platelets as peripheral markers of CNS diseases that glutamate is released upon platelet activation. For example, increased plasma glutamate concentrations have been reported in patients upon admission for stroke, perhaps contributing to an increased thrombotic risk, and following stroke, plasma glutamate concentrations rise and remain elevated for up to two weeks. However, functional studies of peripheral glutamate signaling and its role in vascular physiology are limited to date.
Despite the acknowledged principal role of platelet activation in initiating or exacerbating thrombotic or cardiovascular disease, there are currently few platelet specific drugs available. Thus, there is a need in the art for improved anti-thrombotic therapies that would be useful in disease prevention and treatment.